chr17-63496400-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000789.4(ACE):c.3387T>C(p.Phe1129Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,613,968 control chromosomes in the GnomAD database, including 200,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20476 hom., cov: 34)

Exomes 𝑓: 0.49 ( 180509 hom. )

Consequence

ACE
NM_000789.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.87

Publications

86 publications found

Variant links:

Genes affected

ACE (HGNC:2707): (angiotensin I converting enzyme) This gene encodes an enzyme involved in blood pressure regulation and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II. Angiotensin II is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance. This angiotensin converting enzyme (ACE) also inactivates the vasodilator protein, bradykinin. Accordingly, the encoded enzyme increases blood pressure and is a drug target of ACE inhibitors, which are often prescribed to reduce blood pressure. This enzyme additionally plays a role in fertility through its ability to cleave and release GPI-anchored membrane proteins in spermatozoa. Many studies have associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme. This polymorphism, as well as mutations in this gene, have been implicated in a wide variety of diseases including cardiovascular pathophysiologies, psoriasis, renal disease, stroke, and Alzheimer's disease. Regulation of the homologous ACE2 gene may be involved in progression of disease caused by several human coronaviruses, including SARS-CoV and SARS-CoV-2. Alternative splicing results in multiple transcript variants encoding both somatic (sACE) and male-specific testicular (tACE) isoforms. [provided by RefSeq, Sep 2020]

ACE Gene-Disease associations (from GenCC):

renal tubular dysgenesis of genetic origin
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
intracerebral hemorrhage
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACE links:

ENSG00000264813 (HGNC:):

ENSG00000264813 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 17-63496400-T-C is Benign according to our data. Variant chr17-63496400-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.87 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4 link	c.3387T>C	p.Phe1129Phe	synonymous_variant	Exon 23 of 25	ENST00000290866.10	NP_000780.1	P12821-1B4DKH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10 link	c.3387T>C	p.Phe1129Phe	synonymous_variant	Exon 23 of 25	1	NM_000789.4	ENSP00000290866.4		P12821-1
ENSG00000264813	ENST00000577647.2 link	n.1665T>C		non_coding_transcript_exon_variant	Exon 12 of 31	2		ENSP00000464149.1		F6X3S4

Frequencies

GnomAD3 genomes

AF:

0.516

AC:

78371

AN:

152026

Hom.:

20431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.575

Gnomad AMI

AF:

0.415

Gnomad AMR

AF:

0.554

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.603

Gnomad SAS

AF:

0.626

Gnomad FIN

AF:

0.461

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.475

Gnomad OTH

AF:

0.468

GnomAD2 exomes

AF:

0.522

AC:

131102

AN:

251312

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.587

Gnomad AMR exome

AF:

0.599

Gnomad ASJ exome

AF:

0.372

Gnomad EAS exome

AF:

0.609

Gnomad FIN exome

AF:

0.458

Gnomad NFE exome

AF:

0.475

Gnomad OTH exome

AF:

0.494

GnomAD4 exome

AF:

0.494

AC:

722442

AN:

1461824

Hom.:

180509

Cov.:

AF XY:

0.495

AC XY:

360243

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.576

AC:

19296

AN:

33478

American (AMR)

AF:

0.593

AC:

26504

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.373

AC:

9749

AN:

26136

East Asian (EAS)

AF:

0.584

AC:

23177

AN:

39698

South Asian (SAS)

AF:

0.613

AC:

52830

AN:

86238

European-Finnish (FIN)

AF:

0.458

AC:

24450

AN:

53404

Middle Eastern (MID)

AF:

0.411

AC:

2373

AN:

5768

European-Non Finnish (NFE)

AF:

0.480

AC:

534026

AN:

1111986

Other (OTH)

AF:

0.497

AC:

30037

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

25816

51632

77447

103263

129079

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15988

31976

47964

63952

79940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.516

AC:

78475

AN:

152144

Hom.:

20476

Cov.:

AF XY:

0.516

AC XY:

38407

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.575

AC:

23884

AN:

41518

American (AMR)

AF:

0.555

AC:

8483

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

1298

AN:

3470

East Asian (EAS)

AF:

0.603

AC:

3104

AN:

5146

South Asian (SAS)

AF:

0.626

AC:

3020

AN:

4824

European-Finnish (FIN)

AF:

0.461

AC:

4882

AN:

10596

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.475

AC:

32305

AN:

67978

Other (OTH)

AF:

0.474

AC:

1002

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

2022

4045

6067

8090

10112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.487

Hom.:

76528

Bravo

AF:

0.521

Asia WGS

AF:

0.650

AC:

2260

AN:

3478

EpiCase

AF:

0.465

EpiControl

AF:

0.448

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Renal tubular dysgenesis

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microvascular complications of diabetes, susceptibility to, 3;C3281105:Hemorrhage, intracerebral, susceptibility to;C5681536:Renal tubular dysgenesis of genetic origin

Benign:1

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.46

(source)

DANN

Benign

0.42

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over